Catalysts for many organic reactions of key scientific and industrial significance, such as metathesis of olefins, Mizoroku-Heck, Negishi, Sonogashira, and Suzuki coupling, Noyori asymmetric hydrogenation, or Sharpless asymmetric epoxidation, are in the form of transition metal complexes. One of the greatest problems related to the use of compounds of such type in the synthesis, consists in removal of the metal residues from the products of reactions. This issue is particularly important for the pharmaceutical industry because of restrictive standards related to acceptable heavy metal contents in the biologically active compounds, being below 10 ppm (see, European Medicines Agency, Specification limits for residues of metal catalysts CHMP/SWP/4446/2000, 2008). Many examples of pharmaceutical syntheses demonstrate that this problem is very common and troublesome (see, J. Magano, J. R. Dunetz Chem. Rev. 2011, 111, 2177-2250). This problem may be solved in the following ways:
1. by the means of “classic” purification techniques such as crystallisation, extraction, chromatography;
2. by using of specially designed catalysts that are easily removable after the completed reaction, so called self-scavenging catalysts;
3. by adding transition metal scavengers, i.e., the compounds that bind metals and are easily removable after binding metals, to the post-reaction mixtures or reaction products.
The “classic” purification techniques not always make it possible to obtain a pure product with low metal contents, below 10 ppm. On the other hand, self-scavenging catalysts are either hardly available or expensive. The advantage of metal scavengers resides in their universality. The same scavenger compound can often be used in combination with many types of catalysts of various reactions, thanks to this fact such an approach is more general. An ideal metal scavenger should feature the following properties:
1. to bind various forms of transition metal complexes, at various oxidation states, quickly, irreversibly and quantitatively;
2. to be efficient at slight excess with respect to the catalyst used;
3. to be easily removable in the form bound to the transition metal, by extraction, crystallisation, or chromatography;
4. to be inexpensive and easily obtainable;
5. to be stable in the air and against the moisture, non-toxic, safe, odourless, and conveniently applicable;
6. to be either insoluble or very soluble in typical organic solvents.
Ruthenium scavengers are well-known in the state of the art (see, Table 1 for examples). Some of them are commercially available, but only few of them possess most of the above-mentioned features (see, G. C. Vougioukalakis, Chem. Eur. J. 2012, 18, 8868-8880). Their most important drawbacks comprise the need to use a large excess of the scavenger with respect to the (pre)catalyst (50-500 equivalents), prolonged time required to bind the scavengers to the transition metals (12 hours), high level of contamination of the product with ruthenium after purification (above 10 ppm, see the last column of Table 1), poor solubility in typical, low-polar organic solvents (i.e., diethyl ether, tetrahydrofuran, toluene, dichloromethane), moderate stability in the air, high price.
TABLE 1 Ru contaminationpurificationof the productEntrymetal scavengermol %time [hours]method[ppm]1a 2a430 430   0.16    0.16extraction adding SiO2, filtration670 206 3b25012chromatography over SiO2360 4b25012chromatography over SiO2240 5c 4412chromatography over SiO2220asee, R.H. Grubbs, Tetrahedron Lett., 1999, 40, 4137-4140, bsee, G.I. Georg, Org. Lett., 2001, 3, 1411-1413, csee, S.T. Diver, Org. Lett., 207, 9, 1203-1206.